5 Exubera – Advantages Not an injection!Rapid-acting (comparable to humalog or novorapid).Initial studies suggest that it is at least, if not more “predictable” than existing short-acting analogues.Equivalent HBA1c reductions to sc insulin in both Type 1 and Type 2 DM (and equivalent or slightly less hypos)High patient satisfaction in studies.

8 What is GLP-1? A 31 amino acid peptideCleaved from proglucagon in L-cells in the GI-tract (and neurons in hindbrain/hypothalamus)Secreted in response to meal ingestion (direct luminal and indirect neuronal stimulation)Member of incretin family (GIP, GLP-1 and others)What is GLP-1?Glucagon-like peptide-1 (GLP-1) is a 30 amino acid peptide. It is an incretin hormone that is secreted from L-cells in the gastrointestinal system in response to calorie intake, causing the glucose dependent secretion of insulin. Incretins are chemical excitants that promote pancreatic sections (glucose-dependent insulinotropic polypeptide [GIP] is another example).8

14 GLP-1: effects on the gastrointestinal and central nervous systemsLearning and memory (animal models)GLP-1: effects on the gastrointestinal and central nervous systemsThe net effect of GLP-1’s action on the gastrointestinal system is to delay absorption of food. This is caused by several means, including decreased gastric emptying and acid secretion. For example, the infusion of GLP-1 to generate plasma levels similar to those normally observed following meals delays gastric emptying (Wettergren et al. 1993).Combined, these gastrointestinal effects serve to flatten the meal-related increase in glucose. This may be important in the management of type 2 diabetes because elevated postprandial glucose excursions are a key feature of type 2 diabetes. Reducing this excursion should therefore be an aim of diabetes treatment. Prolonged presence of food in the stomach through delayed gastric emptying may also reduce food intake by increasing the feeling of satiety.Additionally, GLP-1 receptors are present in several areas in the brain. The receptors in the brainstem (area postrema and subfornical organ) are believed to be involved in inducing feelings of satiety, regardless of the presence of food in the gastric system. This action therefore provides another means for decreasing food intake. Recently, GLP-1 has also been shown to improve spatial and associative learning following its intracerebroventricular infusion in the rat (During et al. 2003).ReferencesWettergren et al. Dig Dis Sci 1993;38:665–673Kieffer, Habener. Endocr Rev 1999;20:876–913During et al. Nat Med 2003;9:1173–1179Flint et al. J Clin Invest 1998;101:515–520Gastric emptyingSatietyAcid secretionFood intakeKieffer, Habener. Endocr Rev 1999;20:876–913. Flint et al. J Clin Invest 1998;101:515–520. Wettergren et al. Dig Dis Sci 1993;38:665–673. During et al. Nat Med 2003;9:1173–1179.14

17 Native GLP-1 is rapidly degraded by DPP-IVHuman ileum,GLP-1 producingL-cellsCapillaries,Di-PeptidylPeptidase-IV(DPP-IV)Native GLP-1 is rapidly degraded by DPP-IVGLP-1 is stored in intestinal L-cells. As active GLP-1 is secreted from these cells, it is rapidly degraded by the enzyme dipeptidyl peptidase IV (DPP IV) resulting in the inactive, N-terminally truncated form, GLP-1-(9-36)amide. More than 50% of plasma GLP-1 appears to be in this inactive form.In this slide, immunohistochemical staining shows the very close proximity of active GLP-1 in the L-cells and DPP-IV in the capillaries within the human ileum.ReferencesHansen et al. Endocrinology 1999;140:5356–5363Double immunohistochemical staining for DPP-IV (red) and GLP-1 (green) in the human ileumAdapted from: Hansen et al. Endocrinology 1999;140:5356–5363.17

18 Native GLP-1 has limited clinical value because of its short half-life7379LysDPP-IVHisAlaThrSerPheGluGlyAspValTyrLeuGlnIleTrpArgi.v. bolus GLP-1 (15 nmol/l)Healthy individuals (n=6)1000Type 2 diabetes (n=6)Intact GLP-1 (pmol/l)500Native GLP-1 has limited clinical value because of its short half-lifeThe rapid degradation of GLP-1 into its inactive form by DPP-IV means that when administered as an i.v. bolus, it has a half-life of just 1.5–2.1 minutes. Combined with rapid clearance, this means that the action of GLP-1 has a very limited time span.ReferencesVilsbøll et al. J Clin Endocrinol Metab 2003;88:220–224–5515253545Time (min)Enzymatic cleavageHigh clearance (4–9 l/min)t½ = 1.5–2.1 minutes (i.v. bolus 2.5–25.0 nmol/l)Adapted from Vilsbøll et al. J Clin Endocrinol Metab 2003;88:220–224.18

26 Summaryincretin analogues are a novel treatment modality for T2 diabetesadministration via injectionreduce HbA1c by approximately 1%associated with weight lossgastrointestinal side effects – principally nausealow incidence of hypoglycaemia? will be used if poor glycaemic control on metformin and another agent